Several publications and patent documents are cited in this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these citations is incorporated by reference herein.
There is strong evidence that gene expression can be affected by changes in chromatin structure and the association of DNA with nucleosomes. The acetylation of lysine residues on histone tails by histone acetyltransferases (HATs) neutralizes their charge and decreases the affinity of histones for DNA. Conversely, the deacetylation of these residues by histone deacetylases (HDACs) restores this affinity and can decrease the accessibility of DNA to transcriptional machinery (1). In addition, the Swi/Snf class of proteins can form complexes that can have a profound affect on chromatin structure and gene expression (2). Genetic and biochemical studies have demonstrated that these Swi/Snf proteins can cause ATP-dependent disruption of nucleosome structure at a promoter and enhance the binding of transcription factors to their binding sites (2). The action of these proteins can also lead to nucleosome movement and changes in chromatin conformation, resulting in transcriptional activation (or repression) of a gene or region.
CHD (Chromodomain, Helicase, DNA-binding) genes (3) encode a novel class of Swi/Snf proteins which is characterized by the presence of a Swi/Snf-like helicase-ATPase domain, a DNA binding domain, and a chromodomain motif that can directly effect chromatin structure and gene transcription. Of the four known members of this gene family in humans (CHD1-CHD4) (3), two have been shown to participate in multiprotein complexes responsible for chromatin remodeling. The NuRD (for Nucleosome Remodeling and histone Deacetylation) complex (originally known as Mi2) is a ˜2 MDa complex that consists of at least seven proteins, but the key functional protein in these complexes appears to be either Mi-2a or Mi-2b. Mi-2a is now known as CHD3 and Mi-2b is known as CHD4. There is increasing evidence that CHD protein complexes can have a profound effect on chromatin structure and gene expression, and are thus likely to play an important role in regulating development, cell cycle control, and oncogenesis.